N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

ABSTRACT

N 2  -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 844,188 filedOct. 21, 1977, now U.S. Pat. No. 4,117,127, which in turn is adivisional of Ser. No. 760,745 filed Jan. 19, 1977, now U.S. Pat. No.4,066,773, which is a continuation-in-part of the followingapplications:

Ser. No. 653,217 of Jan. 28, 1976, now U.S. Pat. No. 4,055,651

Ser. No. 713,486 of Aug. 11, 1976, now U.S. Pat. No. 4,073,914

Ser. No. 671,436 of Mar. 29, 1976, now U.S. Pat. No. 4,066,758

Ser. No. 703,704 of July 8, 1976, now U.S. Pat. No. 4,069,323

The Ser. No. 671,436 is a divisional of Ser. No. 622,390 filed Oct. 14,1975, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the discovery of certain new and useful N²-arylsulfonyl-L-argininamides and the pharmaceutically acceptable saltsthereof, which are of especial value in view of their outstandingantithrombotic properties and low toxicities.

2. Description of the Prior Art

In the past, there have been many attempts to obtain new and improvedagents for the treatment of thrombosis. The N²-(p-tolysulfonyl)-L-arginine esters have been found to be one type ofagent which can be used and these have been found to be effective indissolving blood clots. (U.S. Pat. No. 3,622,615, issued Nov. 23, 1971).One family of compounds which have been found to be particularly usefulas highly specific inhibitors of thrombin for the control of thrombosisis the N² -dansyl-L-arginine ester or amide. (Our pending U.S.Application Ser. No. 496,939, filed Aug. 13, 1974 now U.S. Pat. No.3,978,045). However, there is a continuing need for a highly specificinhibitor of thrombin for the control of thrombosis, which exhibitslower toxicity.

SUMMARY OF THE INVENTION

It has now been discovered that N² -arylsulfonyl-L-argininamides exhibitantithrombotic activity and even lower toxicity levels at the samerelative potencies, as compared with the N² -dansyl-L-arginine ester oramide.

The present invention provides an N² -arylsulfonyl-L-argininamide of theformula (I): ##STR1## wherein R is ##STR2## wherein R₁ is hydrogen or C₁-C₅ alkyl; and Ar is 1,2,3,4-tetrahydro-8-quinolyl optionallysubstituted with at least one C₁ -C₃ alkyl.

Also encompassed within this invention are pharmaceutically acceptablesalts thereof.

This invention also relates to a method for inhibiting activity andsuppressing activation of thrombin in vivo in mammals which comprisesadministering to a mammal a pharmaceutically (antithrombotically)effective amount of an N² -arylsulfonyl-L-argininamide or thepharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of N² -arylsulfonyl-L-argininamides ofthe formula (I): ##STR3## wherein R is ##STR4## wherein R₁ is hydrogenor alkyl of 1-5 (preferably 1-3) carbon atoms; and Ar is1,2,3,4-tetrahydro-8-quinolyl optionally substituted with at least one(preferably one or two) alkyl of 1-3 (preferably 1-2) carbon atoms.

Typical compounds of this invention include:

1-[N²-(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid

1-[N²-(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylicacid

1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid

1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylicacid

1-[N²-(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid

1-[N²-(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylicacid

The pharmaceutically acceptable salts of the above compounds are ofcourse also included within the scope of this invention.

For the preparation of the compounds of this invention, various methodscan be employed depending upon the particular starting materials and/orintermediates involved. Successful preparation of these compounds ispossible by way of a synthetic route which is outlined below. ##STR5##In the above formulas, R, Ar and R₁ are as defined herein above; X ishalogen; R'" is a protective group for the α-amino group, such asbenzyloxycarbonyl or tert-butoxycarbonyl; R' and R" are selected fromthe group consisting of hydrogen and protective groups for the guanidinogroup, such as nitro, tosyl, trityl, oxycarbonyl and the like; and atleast one of R' and R" is a protective group for the guanidino group; R₂is lower alkyl such as methyl and ethyl; and Q is 8-quinolyl optionallysubstituted with at least one C₁ -C₃ alkyl, which is corresponding toAr.

The N² -arylsulfonyl-L-argininamide (I) is prepared by removing theN^(G) -substituent from an N^(G) -substituted-N²-quinolylsulfonyl-L-argininamide (IX) by means of hydrogenolysis and, atthe same time, hydrogenating the quinolyl moiety to the corresponding1,2,3,4-tetrahydroquinolyl moiety.

The removal of the nitro group and the oxycarbonyl group, e.g.,benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, is readily accomplished bythe hydrogenolysis.

The hydrogenolysis and hydrogenation are effected in a reaction-inertsolvent, e.g., methanol, ethanol, tetrahydrofuran or dioxane, in thepresence of a hydrogen-activating catalyst, e.g., Raney nickel,palladium, or platinum, ruthenium, rhodium, in a hydrogen atmosphere ata temperature of 0° C. to 200° C. and preferably 50° C. to 150° C. for aperiod of 2 hours to 120 hours.

In general, the hydrogen pressure is in the range of 1 to 100 kg/cm²,and preferably in the range of 5 to 50 kg/cm². It is necessary tocontinue the hydrogenolysis and hydrogenation until a stoichiometricamount of hydrogen is absorbed. The N² -arylsulfonyl-L-argininamides (I)are isolated by filtration of the catalyst followed by evaporation ofthe solvent, and then purified by trituration or recrystallization froma suitable solvent, such as diethyl ether-tetrahydrofuran, diethylether-methanol and water-methanol, or may be chromatographed on silicagel or alumina.

1-(N^(G) -substituted-N²-quinolylsulfonyl-L-arginyl)-2-piperidinecarboxylic acids (IX) can beprepared by hydrolyzing an alkyl 1-(N^(G) -substituted-N²-quinolylsulfonyl-L-arginyl)-2-piperidinecarboxylate (VIII) by aconventional procedure well known in the art.

The alkyl 1-(N^(G) -substituted-N²-quinolylsulfonyl-L-arginyl)-2-piperidinecarboxylate (VIII) can beprepared by condensing an N^(G) -substituted-N² -substituted L-arginine(III) (generally the N^(G) -substituent is nitro or acyl, and the N²-substituent is a protective group for the amino group, such asbenzyloxycarbonyl, tert-butoxycarbonyl, or the like) and a correspondingamino acid derivative (IV), selectively removing only the N²-substituent of an N^(G) -substituted-N² -substituted L-argininamide (V)by means of catalytic hydrogenolysis or acidolysis, and then condensingthe thus obtained N^(G) -substituted-L-argininamide (VI) with aquinolinesulfonyl halide (VII), preferably a chloride in the presence ofa base in a solvent.

The N² -arylsulfonyl-L-argininamide (I) of this invention forms acidaddition salts with any of a variety of inorganic and organic acids.They also form salts with any of a variety of inorganic and organicbases.

The product of the reactions described above can be isolated in the freeform or in the form of salts. In addition, the product can be obtainedas pharmaceutically acceptable acid addition salts by reacting one ofthe free bases with an acid, such as hydrochloric, hydrobromic,hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic,succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. Ina similar manner, the product can be obtained as pharmaceuticallyacceptable salts by reacting one of the free carboxylic acids with abase, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,triethylamine, procaine, dibenzylamine, 1-ephenamine,N,N'-dibenzylethylenediamine, N-ethylpiperidine or the like.

Likewise, treatment of the salts with a base or acid results in aregeneration of the free amide.

As stated above, the N² -arylsulfonyl-L-argininamides, and the saltsthereof of this invention are characterized by their highly specificinhibitory activity in mammals against thrombin as well as by theirsubstantial lack of toxicity, and therefore these compounds are usefulin the determination of thrombin in blood as diagnostic reagents, and/orfor the medical control or prevention of thrombosis.

The compounds of this invention are also useful as an inhibitor ofplatelet aggregation.

The antithrombotic activity of the N² -arylsulfonyl-L-argininamide ofthis invention was compared with that of a known antithrombotic agent,N² -(p-tolylsulfonyl)-L-arginine methyl ester, by determining thefibrinogen coagulation time. The measurement of the fibrinogencoagulation time was conducted as follows:

An 0.8 ml aliquot of a fibrinogen solution, which had been prepared bydissolving 150 mg of bovine fibrinogen (Cohn fraction I) supplied byArmour Inc. in 40 ml of a borate saline buffer (pH 7.4), was mixed with0.1 ml of a borate saline buffer, pH 7.4, (control) or a sample solutionin the same buffer, and 0.1 ml of a thrombin solution (5 units/ml)supplied by Mochida Pharmaceutical Co., Ltd. was added to the solutionsin an ice bath.

Immediately after mixing, the reaction mixture was transferred from theice bath to a bath maintained at 25° C. Coagulation times were taken asthe period between the time of transference to the 25° C. bath and thetime of the first appearance of fibrin threads. In the cases where nodrug samples were added, the coagulation time was 50-55 seconds.

The experimental results are summarized in Table 1. The term"concentration required to prolong the coagulation time by a factor oftwo" is the concentration of an active ingredient required to prolongthe normal coagulation time 50-55 seconds to 100-110 seconds.

The concentration required to prolong the coagulation time by a factorof two for the known antithrombotic agent, N²-(p-tolylsulfonyl)-L-arginine methyl ester, was 1,100 μm. The inhibitorsare shown in Table 1 by indicating R and Ar in the formula (I) and theaddition moiety.

When a solution containing an N² -arylsulfonyl-L-argininamide of thisinvention was administered intravenously into animal bodies, the highantithrombotic activity in the circulating blood was maintained for fromone to three hours. The halflife for decay of the anti-thromboticcompounds of this invention in circulating blood was shown to beapproximately 60 minutes; the physiological conditions of the hostanimals (rats, rabbit, dog and chimpanzee) were well maintained. Theexperimental decrease of fibrinogen in animals caused by infusion ofthrombin was satisfactorily controlled by simultaneous infusion of thecompounds of this invention.

The acute toxicity values (LD₅₀) determined by intravenousadministration of substances of formula (I) in mice (male, 20 g) rangefrom about 100 to 500 milligrams per kilogram of body weight.

Representative LD₅₀ values for 1-N²-(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-4-methyl-2-piperidinecarboxylicacid, 1-N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-4-methyl-2-piperidinecarboxylicacid, 1-N²-(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-4-methyl-2-piperidinecarboxylicacid and 1-N²-(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-4-ethyl-2-piperidinecarboxylicacid are 191, 264, 322 and 132 milligrams per kilogram, respectively.

On the other hand, LD₅₀ values for N² -dansyl-N-butyl-L-argininamide andN² -dansyl-N-methyl-N-butyl-L-argininamide are 10 and 5 milligrams perkilogram, respectively.

The therapeutic agents in this invention may be administered to mammals,including humans, alone or in combination with pharmaceuticallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmaceutical practice.

For example, the compounds may be injected parenterally, that is,intramuscularly, intravenously or subcutaneously. For parenteraladministration, the compounds may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic. The compounds may be administeredorally in the form of tablets, capsules, or granules containing suitableexcipients such as starch, lactose, white sugar and the like.

The compounds may be administered sublingually in the form of troches orlozenges in which each active ingredient is mixed with sugar or cornsyrups, flavoring agents and dyes, and then dehydrated sufficiently tomake the structure suitable for pressing into solid form. The compoundsmay be administered orally in the form of solutions which may containcoloring and flavoring agents. Physicians will determine the dosage ofthe present therapeutic agents which will be most suitable for humans,and dosages vary with the mode of administration and the particularcompound chosen. In addition, the dosage will vary with the particularpatient under treatment.

When the composition is administered orally, a larger quantity of theactive agent will be required to produce the same effect as caused witha smaller quantity given parenterally.

The therapeutic dosage is generally 10-50 mg/kg of active ingredientparenterally, 10-500 mg/kg orally per day.

Having generally described the invention, a more complete understandingcan be obtained by reference to certain specific examples, which areincluded for purposes of illustration only and are not intended to belimiting unless otherwise specified.

It is to be understood that the present invention includespharmaceutical compositions containing a compound of the invention as anactive ingredient. Such compositions may be in the forms describedabove. In particular, the invention includes such compositions in unitdose form.

EXAMPLE 1

(A) Ethyl 1-[N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate

To a stirred solution of 28.3 g of N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginine in 450 ml of dry tetrahydrofuran wereadded in turn 9.0 g of triethylamine and 12.2 g of isobutylchloroformate while keeping the temperature at -20° C. After 10 minutes,to this was added 15.2 g of ethyl 4-methyl-2-piperidinecarboxylate andthe mixture was stirred for 10 minutes at -20° C. At the end of thisperiod, the reaction mixture was warmed to room temperature. The solventwas evaporated and the residue taken up in 400 ml of ethyl acetate, andwashed successively with 200 ml of water, 100 ml of 5% sodiumbicarbonate solution, 100 ml of 10% citric acid solution and 200 ml ofwater. The ethyl acetate solution was dried over anhydrous sodiumsulfate.

The solution was evaporated to give 31.5 g (75 percent) of ethyl1-[N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate inthe form of a syrup.

I.R. (KBr): 3,300, 1,730, 1,680 cm⁻¹

(B) Ethyl 1-[N^(G) -nitro-L-arginyl]-4-methyl-2-piperidinecarboxylatehydrochloride

To a stirred solution of 30 g of ethyl 1-[N^(G) -nitro-N²-(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in 50ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl etherto precipitate a viscous oily product.

This was filtered and washed with dry ethyl ether to give ethyl 1-[N^(G)-nitro-L-arginyl]-4-methyl-2-piperidinecarboxylate hydrochloride as anamorphous solid.

(C) Ethyl 1-[N^(G) -nitro-N²-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate

To a stirred solution of 25 g of ethyl 1-(N^(G)-nitro-L-arginyl)-4-methyl-2-piperidinecarboxylate hydrochloride in 200ml of chloroform were added in turn 18.5 g of triethylamine, and 14.7 gof 3-methyl-8-quinolinesulfonyl chloride at 5° C., and stirring wascontinued for 3 hours at room temperature. At the end of this period,the solution was washed twice with 50 ml of water.

The chloroform solution was dried over anhydrous sodium sulfate. Uponevaporation of the solvent, the residue was chromatographed on 50 g ofsilica gel packed in chloroform, washed with chloroform and eluted with3% methanol-chloroform. The fraction eluted from 3% methanol-chloroformwas evaporated to give 32.1 g (91 percent) of ethyl 1-[N^(G) -nitro-N²-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylatein the form of an amorphous solid.

I.R. (KBr): 3,250, 1,725, 1,640 cm⁻¹

(D) 1-[N^(G) -nitro-N²-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid

A solution of 30 g of ethyl 1-[N^(G) -nitro-N²-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylatein 100 ml of ethanol and 100 ml of 1 N sodium hydroxide solution wasstirred for 24 hrs at room temperature. At the end of this period, thesolution was neutralized with 1 N hydrochloric acid and thenconcentrated to 70 ml.

The solution was adjusted to pH 11 with 1 N sodium hydroxide solution,washed three times with 100 ml of ethyl acetate, acidified with 1 Nhydrochloric acid and then extracted three times with 100 ml ofchloroform. The combined chloroform solution was dried over anhydroussodium sulfate and evaporated to give 28.0 g (97 percent) of 1-[N^(G)-nitro-N²-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid as an amorphous solid.

IR (KBr): 3,300, 1,720, 1,630 cm⁻¹ Analysis Calcd. for C₂₃ H₃₁ N₇ O₇ S(percent): C, 50.26; H, 5.69; N, 17.84 Found (percent) C, 50.00; H,5.50; N, 17.49

(E) 1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid

To a solution of 3.00 g of 1-[N^(G) -nitro-N²-(3-methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid in 50 ml of ethanol was added 0.5 g of palladium black and then themixture was shaken under 10 kg/cm² hydrogen pressure at 100° C. for 8hrs. At the end of this period, the ethanol solution was filtered toremove the catalyst and evaporated to give 2.50 g (90 percent) of 1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid as an amorphous solid.

IR (KBr): 3,400, 1,620, 1,460, 1,380 cm⁻¹ NMR: 100 MHz in CD₃ ODδ-value; 6.5 (triplet 1H) 7.1 (doublet 1H), 7.4 (doublet 1H)

Analysis Calcd. for C₂₃ H₃₆ N₆ O₅ S (percent): C, 54.31; H, 7.13; N,16.52 Found (percent) C, 54.01; H, 6.98; N, 16.61

Various other N² -arylsulfonyl-L-argininamides were synthesized inaccordance with the procedure of the above example, and the test resultsare summarized in Table 1.

                                      TABLE 1                                     __________________________________________________________________________     Sample                                                                            ##STR6##                Concen- tration required to prolong the                                       coagulation time by a factor of                                                       proper-Physical                                                                    Lower: FoundUpper:                                                           CalculatedElemental                                                                      I.R.                      valueN.M.R.                                               (ppm)δ        No. Ar            R          (μM)                                                                              ties C  H   N  (cm.sup.-1)                                                                         (CD.sub.3            __________________________________________________________________________                                                             OD)                       ##STR7##                                                                                    ##STR8##  0.45   powder                                                                             54.31 54.21                                                                      7.13 6.98                                                                         16.52 16.38                                                                      3,380, 1,620 1,460,                                                           1,375 6.5 (t, 1H) 7.1                                                               (d, 1H) 7.4 (d,                                                               1H)                  2                                                                                  ##STR9##     "          0.08   powder                                                                             54.31 54.01                                                                      7.13 6.98                                                                         16.52 16.61                                                                      3,400, 1,620 1,460,                                                           1,380 6.5 (t, 1H) 7.1                                                               (d, 1H) 7.4 (d,                                                               1H)                  3                                                                                  ##STR10##    "          0.2    powder                                                                             54.31 54.50                                                                      7.13 7.01                                                                         16.52 16.29                                                                      3,380, 1,620 1,380,                                                           1,160 6.5 (t, 1H) 7.2                                                               (d, 1H) 7.4 (d,                                                               1H)                  4                                                                                  ##STR11##    "          1.8    powder                                                                             54.31 54.28                                                                      7.13 7.13                                                                         16.52 16.40                                                                      3,380, 1,620 1,380,                                                           1,285 6.9 (s, 1H) 7.3                                                               (s, 1H)              5                                                                                  ##STR12##    "          5.5    powder                                                                             55.15  55.20                                                                     7.33 7.29                                                                         16.08 16.00                                                                      3,350, 1,620 1,380,                                                           1,150 6.5 (t, 1H) 7.1                                                               (t, 1H) 7.4 (t,                                                               1H)                  6                                                                                  ##STR13##    "          0.06   powder                                                                             55.15 55.11                                                                      7.33 7.40                                                                         16.08 15.88                                                                      3,375, 1,620 1,460,                                                           1,380 6.6 (t, 1H) 7.2                                                               (d, 1H) 7.4 (d,                                                               1H)                  7                                                                                  ##STR14##    "          0.45   powder                                                                             53.42 53.12                                                                      6.93 6.63                                                                         16.99 16.59                                                                      3,380, 1,620 1,460,                                                           1,380 6.6 (d, 1H) 7.1                                                               (d, 1H) 7.4 (d,                                                               1H)                  8                                                                                  ##STR15##                                                                                   ##STR16## 0.45   powder                                                                             54.31 54.20                                                                      7.13 7.19                                                                         16.52 16.41                                                                      3,380, 1,620 1,460                                                            1,380 6.6 (d, 1H) 7.1                                                               (d, 1H) 7.4 (d,                                                               1H)                  9                                                                                  ##STR17##    "                 powder                                                                             55.15 55.07                                                                      7.33 7.03                                                                         16.08 16.38                                                                      3,380, 1,620 1,460,                                                           1,380 6.5 (t, 1H) 7.2                                                               (d, 1H) 7.4 (d,                                                               1H)                  10                                                                                 ##STR18##    "                 powder                                                                             55.95 55.69                                                                      7.51 7.28                                                                         15.66 15.51                                                                      3,380, 1,620 1,460,                                                           1,380 6.5 (t, 1H) 7.2                                                               (d, 1H) 7.4 (d,                                                               1H)                  11                                                                                 ##STR19##                                                                                   ##STR20##        powder                                                                             53.42 53.28                                                                      6.93 6.63                                                                         16.99 16.69                                                                      3,380, 1,620 1,460,                                                           1,380 6.6 (d, 1H) 7.1                                                               (d, 1H) 7.4 (d,                                                               1H)                  __________________________________________________________________________

EXAMPLE 2

Tablets suitable for oral administration

Tablets containing the ingredients indicated below may be prepared byconventional techniques.

    ______________________________________                                                                Amount per tablet                                     Ingredient              (mg)                                                  ______________________________________                                        1-[N.sup.2 -(1,2,3,4-tetrahydro-8-                                            quinolinesulfonyl)-L-arginyl]-4-methyl-                                                               250                                                   2-piperidinecarboxylic acid                                                   Lactose                 140                                                   Corn starch             35                                                    Talcum                  20                                                    Magnesium stearate       5                                                    Total                   450 mg                                                ______________________________________                                    

EXAMPLE 3

Capsules for oral administration

Capsules of the below were made up by thoroughly mixing together batchesof the ingredients and filling hard gelatin capsules with the mixture.

    ______________________________________                                                               Amount per capsule                                     Ingredient             (mg)                                                   ______________________________________                                        1-[N.sup.2 -(1,2,3,4-tetrahydro-8-                                            quinolinesulfonyl)-L-arginyl]-4-methyl-                                                              250                                                    2-piperidinecarboxylic acid                                                   Lactose                250                                                    Total                  500 mg                                                 ______________________________________                                    

EXAMPLE 4

Sterile solution for infusion

The following ingredients are dissolved in water for intravenousperfusion and the resulting solution is then sterilized.

    ______________________________________                                        Ingredients                Amount (g)                                         ______________________________________                                        1-[N.sup.2 -(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-                       arginyl]-4-methyl-2-piperidinecarboxylic acid                                                            25                                                 Buffer system              As desired                                         Glucose                    25                                                 Distilled water            500                                                ______________________________________                                    

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit of the invention as setforth herein.

What is claimed as new and intended to be covered by Letters Patent ofthe United States:
 1. An N² -arylsulfonyl-L-argininamide of the formula(I): ##STR21## wherein R is ##STR22## wherein R₁ is hydrogen or C₁ -C₅alkyl; and Ar is 1,2,3,4-tetrahydro-8-quinolyl optionally substitutedwith at least one C₁ -C₃ alkyl.
 2. The compound of claim 1 wherein R₁ ishydrogen or C₁ -C₃ alkyl and Ar is 1,2,3,4-tetrahydro-8-quinolyloptionally substituted with at least one C₁ -C₂ alkyl.
 3. The compoundof claim 2, which is 1-[N²-(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid.
 4. The compound of claim 2, which is 1-[N²-(1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylicacid.
 5. The compound of claim 2, which is 1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid.
 6. The compound of claim 2, which is 1-[N²-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylicacid.
 7. The compound of claim 2, which is 1-[N²-(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylicacid.
 8. The compound of claim 2, which is 1-[N²-(3-ethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-ethyl-2-piperidinecarboxylicacid.